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Quantitative Assessment of Plasmodium Falciparum PNAS PLUS Sexual Development Reveals Potent Transmission- Blocking Activity by Methylene Blue

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Quantitative Assessment of Plasmodium Falciparum PNAS PLUS Sexual Development Reveals Potent Transmission- Blocking Activity by Methylene Blue Quantitative assessment of Plasmodium falciparum PNAS PLUS sexual development reveals potent transmission- blocking activity by methylene blue Sophie H. Adjalleya,1, Geoffrey L. Johnstona,b, Tao Lic, Richard T. Eastmana,2, Eric H. Eklanda, Abraham G. Eappenc, Adam Richmanc, B. Kim Lee Simc, Marcus C. S. Leea, Stephen L. Hoffmanc, and David A. Fidocka,d,3 aDepartment of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032; bSchool of International and Public Affairs, Columbia University, New York, NY 10027; cSanaria, Inc., Rockville, MD 20850; and dDivision of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 Edited* by Thomas E. Wellems, National Institutes of Health, Bethesda, MD, and approved October 5, 2011 (received for review July 25, 2011) Clinical studies and mathematical models predict that, to achieve the course of infection, allowing gametocytes to mature and malaria elimination, combination therapies will need to incorpo- continue the transmission cycle (4, 5). rate drugs that block the transmission of Plasmodium falciparum Most of the available information on the impact of existing sexual stage parasites to mosquito vectors. Efforts to measure the antimalarials on gametocyte development has been gathered activity of existing antimalarials on intraerythrocytic sexual stage from field-based clinical trials, and in vitro studies remain sparse gametocytes and identify transmission-blocking agents have, until (6). Activity against immature gametocytes has been observed now, been hindered by a lack of quantitative assays. Here, we with a number of drugs that target metabolic pathways in asexual report an experimental system using P. falciparum lines that stably blood stage parasites. These drugs include chloroquine and express gametocyte-specific GFP-luciferase reporters, which en- quinine, which interfere with heme detoxification, and atova- able the assessment of dose- and time-dependent drug action on quone, which targets mitochondrial electron transport (6, 7). gametocyte maturation and transmission. These studies reveal ac- Artemisinins have also been observed to inhibit immature sexual tivity of the first-line antimalarial dihydroartemisinin and the part- stages and reduce gametocyte carriage in infected human hosts ner drugs lumefantrine and pyronaridine against early gametocyte (8, 9). The experimental design of many of the studies, however, MICROBIOLOGY stages, along with moderate inhibition of mature gametocyte has often made it difficult to distinguish between direct game- transmission to Anopheles mosquitoes. The other partner agents tocytocidal activity and the antiasexual properties that reduce the monodesethyl-amodiaquine and piperaquine showed activity only pool of parasites available to initiate gametocytogenesis. Earlier against immature gametocytes. Our data also identify methylene in vitro evaluations of drug gametocytocidal activity typically blue as a potent inhibitor of gametocyte development across relied on laborious, subjective microscopic observations of par- all stages. This thiazine dye almost fully abolishes P. falciparum asite morphology to assess cell viability (6). Recent advances transmission to mosquitoes at concentrations readily achievable in include the use of hydroethidine or alamarBlue as fluorescent humans, highlighting the potential of this chemical class to reduce markers of metabolic activity (10, 11) or GFP reporter lines to the spread of malaria. assess commitment to gametocytogenesis (12, 13), notably after antimalarial drug treatment of asexual forms (10). These meth- artemisinin-based combination therapies | transfection ods, however, have yet to be exploited to assess dose-dependent drug effects over time or define rates of action with purified, ith ∼225 million individuals infected and an estimated mature gametocyte populations. Also, these studies have not W780,000 deaths annually—largely among African children— measured drug-mediated inhibition of P. falciparum transmission Plasmodium falciparum malaria remains one of the world’s most to Anopheles, a technically challenging endeavor. devastating diseases. Encouragingly, in recent years, the global Here, we have engineered a set of P. falciparum lines ex- fi adoption of highly effective artemisinin-based combination pressing stably integrated gametocyte-speci c GFP-luciferase fi therapies (ACTs) as first-line treatments and the distribution of reporters, and we have developed assays to speci cally monitor fi long-lasting insecticide-treated bednets have helped reduce the parasite sexual development throughout the ve stages of game- prevalence of malaria in many endemic settings (1). This recent tocytogenesis and determine the kinetics of gametocytocidal success contributed to the launch in 2007 of a new campaign action of antimalarial agents. Luciferase-based assays permitted of malaria eradication (2). Clinical reports and mathematical quantitative assessment of the effects of key primary and partner models show that additional reductions in the incidence of dis- components of ACTs on P. falciparum gametocyte maturation. ease can be achieved with interventions combining vector control Select compounds were then further investigated for their ability approaches and treatments that not only cure patients but also decrease transmission (3). Current antimalarials reduce P. falciparum malaria-associated morbidity and mortality by targeting the pathogenic asexual Author contributions: S.H.A., T.L., A.R., M.C.S.L., and D.A.F. designed research; S.H.A., T.L., R.T.E., A.G.E., and M.C.S.L. performed research; S.H.A., G.L.J., E.H.E., A.R., B.K.L.S., S.L.H., blood stages within infected erythrocytes. This activity indirectly and D.A.F. analyzed data; and S.H.A., G.L.J., E.H.E., M.C.S.L., S.L.H., and D.A.F. wrote impacts parasite transmission to its Anopheles mosquito vector the paper. by limiting the number of asexual forms that can differentiate The authors declare no conflict of interest. into mature intraerythrocytic gametocytes. Nevertheless, patients *This Direct Submission article had a prearranged editor. cleared of asexual parasites can still transmit surviving game- 1Present address: Genome Biology Unit, European Molecular Biology Laboratory, 69117 tocytes. Ideal combination therapies would, thus, target both the Heidelberg, Germany. rapidly replicating asexual stages and the less metabolically ac- 2Present address: Laboratory of Malaria and Vector Research, National Institute of Allergy tive, nonreplicating mature gametocytes. This ideal combination and Infectious Diseases, National Institutes of Health, Rockville, MD 20852. is of particular relevance in highly endemic regions, where 3To whom correspondence should be addressed. E-mail: [email protected]. P. falciparum infections are often asymptomatic and thus, go This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. untreated and where clinical symptoms tend to develop late in 1073/pnas.1112037108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1112037108 PNAS Early Edition | 1of10 Downloaded by guest on September 30, 2021 to inhibit gametocyte transmission to Anopheles vectors. Our plasmids and signal heterogeneity between parasites. Here, results show that ACT compounds in clinical use are generally transgene integration was applied to the NF54 strain, which active against immature gametocytes. We also observed partial produces highly infectious gametocytes and is being used in activity of dihydroartemisinin (DHA) against late stage game- human malaria vaccine trials (16). Our integration strategy was tocytes, consistent with a reduction in the number of oocysts in designed to eliminate the selectable marker that might otherwise mosquitoes fed on DHA-treated gametocytes. Exquisite potency interfere with antimalarial modes of action. was observed against early and mature gametocytes with the Bxb1 integrase catalyzes homology-directed recombination synthetic dye methylene blue (MB), which also almost fully between a short attP site and a target attB site. NF54 parasites blocked transmission. These results provide the foundation to containing an attB site were generated by transforming asexual identify transmission-blocking agents that can be integrated into blood stages with the pCC-cg6-attB plasmid, which contains an curative combination therapies. attB site cloned between sequences homologous to the cg6 gene along with the human dhfr-positive selectable marker and the Results cdup-negative marker (Fig. 1A). After selection for human dhfr + Engineering of Unmarked NF54attB Recombinant Parasites Amenable (using the antifolate WR99210), PCR was used to detect attB to Site-Specific Recombination. To produce P. falciparum reporter integrants that resulted from single cross-over recombination on lines expressing GFP-luciferase under the control of gametocyte- the 3′ side of cg6. Integration was confirmed by Southern blot specific promoters, we used Bxb1 mycobacteriophage integrase- hybridization (Fig. 1B), and clones were obtained by limiting mediated recombination to deliver transgenes into the P. falci- dilution. After removal of WR99210, the negative selection parum genome (14). Prior strategies have used transgenes on agent 5-fluorocytosine was applied to select for intralocus re- episomally replicating plasmids (13, 15), where the absence of combination between duplicated cg6 5′ sequences, leading to selection during
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